Professor David Jane

Development of pharmacological tools for glutamate receptors

Glutamate receptors are the major excitatory synaptic receptors in brain and spinal cord. They are of two major types, ionotropic and metabotropic glutamate receptors.

Ionotropic glutamate receptors (iGluRs), which mediate fast synaptic responses via ion fluxes, are further subdivided into three main groups characterised by their preferential agonists N-methyl-D-aspartate (NMDA), kainate and (S)-a-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA). The work of the group combines chemistry and pharmacology. We have synthesized and pharmacologically characterised a range of selective agonists and/or antagonists for each of these receptors by means of which the synaptic receptors in various brain and spinal cord pathways can be identified.

The work of the group can be split into three key areas:

Design of novel glutamate receptor agonists and antagonists. The group has recently acquired state of the art computer-aided molecular modelling facilities to take advantage of the recently published X-ray crystal structures of glutamate receptor ligand binding cores.

Chemical synthesis of target amino acids. The group is based in a recently refurbished chemistry laboratory and has access to all the facilities of the adjacent School of Chemistry. The chemistry undertaken by the group is very varied and includes the synthesis of heterocyclic compounds and the synthesis of novel analogues of natural products. As the target amino acids are usually chiral a number of techniques are used to obtain separate enantiomers including asymmetric synthesis and resolution by crystallisation of diastereoisomers and by chiral HPLC.

Pharmacological characterisation of novel compounds. Assays using cloned mGlu and iGlu receptors subtypes are currently used to characterise compounds synthesised by chemists within the group. In collaboration with other groups in Bristol (e.g. Graham Collingridge and Elek Molnar) and elsewhere the pharmacological tools we have developed are used to understand the physiological roles of individual glutamate receptor subtypes.